Project II: New Medications for Cocaine, Heron and Polydrug Abuse is part of a new PO1 proposal entitled Cocaine and Polydrug Abuse: New Medication Strategies. The purpose of this project is to assess candidate medications for the treatment of polydrug abuse involving both cocaine and opiates. Abuse of cocaine and opiates continues to be a significant public health problem, and polydrug abuse involving combinations of cocaine and opiates. Abuse of cocaine and opiates continues to be a significant public health problem, and polydrug abuse involving combinations of cocaine and opiates (known as a 'speedball") is one prevalent form of multiple drug use. Although effective medications exist for the treatment of opiate abuse, there is no uniformly effective medications for the treatment of cocaine abuse, and polydrug abuse involving both cocaine and opiates is especially refractory to treatment. Our preliminary studies suggest that treatment of speedball abuse may be best accomplished with medication combinations that target both dopaminergic mechanisms underlying the effects of cocaine and opioid mechanisms underlying the effects of opiates. Accordingly, we propose to assess the effects of medication combinations as candidate treatments for speedball abuse. The compounds proposed for study are divided into two categories. To target the cocaine component of the speedball, we propose to study dopamine reuptake inhibitors (indratraline, RTI-113, GBR12909), dopamine D1 receptor agonists (SFKF82958, SKF77434) and a dopamine D1 receptor antagonist (SCH39166). To target the opiate component, we propose to study the high efficacy mu agonist methadone, the intermediate efficacy mu agonist buprenorphine and the opioid antagonist nalmefene. Dopaminergic and opioid compounds will be studied alone and in combination in monkeys trained to discriminate or to self-administer cocaine alone, heroin alone, or cocaine/heroin combinations. Drug self-administration will also be examined during withdrawal from chronic medication delivery. Treatment effects on drug- maintained responding under a progressive ratio schedule will also be examined. The reinforcing effects of the most effective and selective medications or medical combinations will be assessed using drug self- administration substitution studies. This comprehensive series of studies will advance our understanding of the neurobiology of speedball abuse and the relative effects of candidate treatment medications.